Human consumption of ephedrine and caffeine in combination has been associated with a number of adverse effects including changes in the electrocardiogram (ECG), myocardial infarction, hyperthermia, and in rare instances, death. The purpose of this study was to investigate the potential mechanisms associated with the cardiotoxicity of ephedrine and caffeine ingested in combination. Seven and 14 week old Fischer (F344) rats were treated with ephedrine in combination with caffeine. Significantly different increases in heart rate and temperature were observed between 7 and 14 week old rats. Fourteen week old rats treated with ephedrine and caffeine had higher expression of beta-1-AR, and UCPs 2 and 3. Of the 14 week old rats treated with ephedrine and caffeine, almost half died within 3-5 hours of dosing, while all of the similarly dosed 7 week old and 14 week old rats treated with vehicle, ephedrine alone or caffeine alone did not die. Histopathological studies suggested interstitial hemorrhage and myofibrillar necrosis. The differential responses between age groups were particularly notable in the rats that died compared with either the 14 week old rats that did not die or the 7 week old rats. Combined dosing of ephedrine and caffeine increased the risk of myocardial ischemic injury due to an oxygen supply-demand imbalance. Ischemic injury, changes in cardiac function and an exacerbated hyperthermic